White matter microstructure disruption is correlated with amyloid burden in subjects with subjective cognitive decline.

Fundació ACE Healthy Brain Initiative.

Introduction

Methods

Conclusions:

Acknowledgements: We are obliged to Trinitat Port-Carbó and her family for their support of the Fundació ACE research programs. Funds from Fundació ACE. Institut Català de Neurociències Aplicades, Grifols ®, Piramal ® and Araclon Biotech® are supporting FACEHBI.

*Corrresponding author: Oscar Sotolongo-Grau. Fundació ACE. Gran Via de Carles III 85 bis. 08024. Barcelona. Spain

O. Rodriguez-Gomez1 MD, A. Sanabria1 Msc, A. Pérez-Cordón1 Msc, D. Sánchez-Ruíz¹ MD, S. Ruiz1, M. Tarragona1, J. Pavía2 PhD, F. Campos2 Msc, A. Vivas3 MD, M. Gómez3 MD, M. Tejero3 RT,

M. Alegret1 PhD, A. Espinosa1 Msc, G. Ortega1 PhD, C. Abdelnour1 MD, I. Hernández1 MD PhD, A. Ruiz1 MD PhD J. Giménez3 MD, F. Lomeña2 MD, L. Tárraga1 Msc, O. Sotolongo-Grau1 PhD, M.

Boada1 MD PhD

Results

1. Alzheimer Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain2. Servei de Medicina Nuclear, Hospital Clínic i Provincial. Barcelona, Spain3. Departament de Diagnòstic per la Imatge. Clínica Corachan, Barcelona, Spain

The natural history of Alzheimer´s disease (AD) seems to begin several years before the onset of clinical symptoms. Imaging biomarkers can detect some of the key pathophysiological features of AD even before the clinical phase. Amyloid burden can be characterized using positron emission tomography (PET) with amyloid tracers such as Florbetaben (FBB). Magnetic resonance imaging (MRI) can show brain atrophy. Alteration of the white matter microstructure measured by diffusion tensor imaging (DTI ) could be also an early phenomenon in the pathophysiology of AD. Subjective cognitive decline (SCD) has been proposed as a marker of neurodegeneration in cognitively normal elderly individuals. Thus, population with SCD could be an appropriate target for research studies of preclinical AD. Fundació ACE Healthy Brain Initiative (FACEHBI) is an ongoing longitudinal cohort study of individuals with SCD. FACEHBI has been registered as a clinical trial (EUDRACT 2014-000798-38).

Inclusion criteria: 1) older than 49 years; 2) MFE-30≥8; 3) MMSE ≥ 27; 4) CDR =0; 5) performance in a comprehensive neuropsychological battery (NBACE) within the normal range according to age and education; 6) HAD Scale <11.MRI, DTI and FBB-PET were acquired for every subject in a 30 days window after the visit. The MRI T1-3D of 1x1x1 mm voxel size and DTI scans were acquired with a 1.5T Siemens© Magneton Aera. FBB-PET scans were acquired in a Siemens© Biograph molecular-CT machine. Four FBB-PET scans of 5 minutes were acquired after 80 minutes post injection of 300 Mbq of Florbetaben(18F) radio tracer (NeuraCeq©). MRI cortical and subcortical segmentation was carried on with Freesurfer 5.3. Hippocampus volume, cortex mean thickness and white matter hypointensities (WMH) were determined from the segmentation. FBB-PET scans were processed with FSL 5.0 suite. The FBB-PET images were coregistered onto structural images. Standard uptake value ratio (SUVR) were determined as the mean value of the cortical regions segmented on MRI and normalized by the cerebellum gray matter. DTI images were also processed with FSL. The images were eddy corrected, skull stripped, fitted to a diffusion tensor model for each voxel and registered in the standard space template FMRIB58. Fractional anisotropy (FA) and mean diffusivity (MD) was calculated for the regions of the white matter John Hopkins University (JHU) Atlas. The hippocampus volume was calculated as the mean value between left and right hemispheres and corrected by intracranial volume (aHV). The cortex mean thickness was calculated as the mean value between left and right hemispheres. Statistical treatment of the data was carried on with R statistical software. Pearson regressions for FBB SUVR were made for age, WMH, hippocampus volume, cortex mean thickness and mean diffusivity of JHU regions of interest (ROI) in order to check if relevant relationships exist between those variables. A second attempt of Pearson regressions was made for FBB cortical retention and mean diffusivity of some promising JHU ROIs (body of corpus callosum, splenium of corpus callosum) taking age, gender, education and WMH as covariates.

Mean diffusivity in the corpus callosum was correlated with amyloid burden. Hippocampal atrophy and mean cortical thickness were not correlated with FBB SUVR in our study. This finding suggests that white matter integrity disruption of interhemispheric connection tracts could be an early phenomenon in the pathophysiology of Alzheimer's disease, even in the absence of significant grey matter atrophy. Further studies are needed to confirm this finding.Subjects are divided into three different groups regarding amyloid burden and vascular lesions. Due to the healthy cognitive conditions required as inclusion criteria a combination of both factors is no allowed. At the same time amyloid burden seems to be independent from age in those subjects.

Figure 1: Relationship of HV, CMT and WMH with age. WMH was fitted as an exponential function of age with nWMH as covariable.

White Matter ROIWhite Matter ROI R2R2 p-valuep-value

Body of corpus callosumBody of corpus callosum 0.160.16 0.020.02

Splenium of corpus callosumSplenium of corpus callosum 0.100.10 0.040.04

Cingulum cingulate gyrusCingulum cingulate gyrus 0.100.10 0.080.08

Cingulum hippocampusCingulum hippocampus 0.100.10 0.090.09

Table 1. Linear regression for FBB and mean diffusivity at different white matter ROI with age, gender, education and WMH as covariables.

Figure 2: Characterization of amyloid burden with PET-FBB along the study. Only 7% of the subjects could be classified as Amyloid positive with the usual 1.45 cut-off. FBB SUVR seems to be independent from age.

Figure 4: Relationship between amyloid burden and mean diffusivity of Body of corpus callosum and Splenium of corpus callosum.

Figure 3: White matter lesions and amyloid burden seems to be mutually exclusive along the subjects of the study. Notice that the presence of both seems to be an exclusion factor for the study.